Biphenyl compounds



Patented July 25, 1950 UNITED STATES PATENT OFFICE BIPHENYL COMPOUNDS Louis L. Bambas, Grosse Pointe Woods, Micln, as-

signor to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application March as, 1949, Serial No. sans m I hn- H-on,o Ra

while the intermediates used in their preparation are biphenylyl-a-acylamido-s-hydroxyethyl ke-. tone compounds having the formula,

0 NH-Aeyl a Lhasa...

and biphenylyl aminomethyl ketone compounds having the formula,

mi. 1 isms LQGI 8 Claims. (Cl. 260-562) equivalent of an inorganic or organic acid. The term acyl as used herein includes saturated and unsaturated lower aliphatic acyl, halogen sublower aliphatic acyl, cyano substituted lower aliphatie acyl, ether substituted lower aliphatic acyl, ester substituted lower aliphatic acyl, benzoyl, substituted benzoyl, araliphatle acyl, furoyl, V pyridinoyl and the like radicals.

In its broader aspects the invention also includes the acid addition salts of the free bases of the 1-biphenylyl-2-aminopropane-1,3-diol and '40 stituted lower aliphatic acyl, carboxy substituted some examples of such acid addition salts are the hydrochloride, hydrobromide, hydroiodide, sulfate, suliamate, phosphate, acetate, citrate, oxalate, succinate, benzoate, tartrate, phthalate, maleate, camphor sulfonic acid, bromcamphor sulfonic acid and the like.

It will be appreciated by those skilled in the art that the end products or the invention and their derivatives can exist in structural as well as optical isomeric forms. The term structural" isomer or form as used herein refers to the .cis or trans, that is, the planar relationship of the polar groups on the two asymmetric carbon atoms. To differentiate between these two possible diastereoisomers I will subsequently refer to the cis compounds as the regular (reg.) series or form and to the trans diastereiosomers as the pseudo (1') series or form. Such cis compounds are products wherein the two most highly polar of the groups on the asymmetric carbon atoms lie on the same side of the plane of the two carbon atoms. Con-' versely, the trans or pseudo compounds are those wherein the two most highly polar groups lie on opposite sides of the plane of the two carbon atoms.

Both the regular and pseudo forms exist as racemates of the optically active dextro (d) and levo (1) rotatory isomers as well as in the form of the individual or separated dextro (d) and levo (1) optical isomers.

Because of the difliculty of representing these structural differences in graphic formulae the customary structural formulae will be used in both the specification and claims and a notation placed below or to the side of the formula to designate the particular structural and optical configuration of the compound. Where the formula represents the unresolved mixture of the structural and optical isomers the notation unresolved will be used. However, it should be expressly understood that where no notation appears with a structural formula the formula is to be interpreted in its generic sense, that is, as representing the (1)-p, (d) -11, (1)-reg. or (d)-reg. isomers 'in separated form as well as the (d1) ,0 or the (d1) -reg. optical racemates or the total unresolved "mixture of the structural and optical isomers.

' Such a formula does not'merely represent the unresolved mixture-oi the isomers.

and biphenylyl aminomethyl ketone compounds. My process for obtaining the compounds ofithe invention may be diagrammatically illustrated as follows:

present in such reaction media is'to remove the formaldehyde formed in the reaction as the acetal and thus prevent its reaction with either the starting material or final product. Reaction mixtures consisting of or containing alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like produce particularly good Step! 1 ydro y results.

. The hydrolysis reaction can be carried out at o temperatures varying from about 0 to 110 C. g However, I prefer to use a temperature of about CHNH"HY to C. since in this temperature range the L I reaction proceeds at a reasonable rate and the danger of decomposition of the starting mate- Step n l acylation 15 rial and/or the final product is almost at a minimum. 0 Step II of the process comprises converting the g mineral acid addition salt of the biphenylyl ENE-MY] aminomethyl ketone obtained in Step I to the cor- L in responding biphenylylacylamidomethyl ketone of formula,

0 0 R. -CHiNH-Acyl StepIII \H 25 l- J [81mm 9 mysfl In carrying out this acylation an acid addition 0 NH-Acyl O NH-Acyl R, r C C -Jm-omon 1c.. C C 1 -JlH-CHaO-Acyl lacylation BtepV p i 1 1 p l l l OH NH-Acyl 0H NH-Aw] R. r -dn-cn-cmon R.- 1 H-H-CHaO-Acyi J 'e cylation[d"| I hydrolysis [d] r r r l l acylation [c1 mammal) acylation [e1 a ylation [a] m tlonlll hydrolysis =1 I 0-Acyl 0H NH, NH-Acyl R. C HH-CH10H B. lHJ7HCH:0-Acyi I J [C3D] hydrolysis [c] where X is a halogen atom, HY represents one equivalent of an inorganic mineral acid and R and n have the same significance as given above. Step I of my process comprises hydrolyzing a biphenylyl halomethyl ketone-hexamethylenetetramine complex of formula,

O -CHKCH!) aNrX to the corresponding biphenylyl aminomethyl ketone acid addition salt. This hydrolysis may be carried out in aqueous or non-aqueous reaction mixtures using an inorganic mineral acid as the hydrolytic agent. Any mineral acid can be used. For example, hydrochloric, hydrobromic, hydroiodic, sulfuric or phosphoric acids can be employed. Regardless of the acid selected as the hydrolysis catalyst, the biphenylyl aminomethyl ketone acid addition salt formed consists principally of the salt corresponding to the acid used in the hydrolysis. For the best yields of the deiired products it is preferable to use an alcoholic 'eaction medium. The function of the alcohol salt of the biphenylyl aminomethyl ketone must be employed as the starting material since the free bases of these amino ketones are rather unstable. However, in order for the acylation reaction to take place the biphenylyl aminomethyl ketone compound must be in the form of its free base or an organic acid addition salt and it is therefore necessary to generate simultaneously the free base or the organic acid addition salt in the reaction mixture and to acylate it. This is accomplished by carrying out the reaction in the presence of a weakly alkaline substance such as an alkali metal salt of an organic acid, an alkali or alkaline earth metal carbonate or bicarbonate, a tertiary organic base, a hydroxide of an amphoteric metal, calcium hydroxide and the like. Some specific examples of such weakly alkaline substances are sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, calcium carbonate, magnesium carbonate, pyridine, quinoline, triethylamine and aluminum hydroxide.

As acylating agents acyl halide or acyl anhydrides can be employed in conjunction with either aqueous or non-aqueous reaction mediums.

hours. the reaction proceeds very rapidly and is usually The temperature of the reaction is not partlcularly critlcal and can be varied over a conslderable range without any significant deleterious effect upon the yields of the final products.

In general, temperatures varying from C. to

In carrying out this condensation the formaldehyde may be supplied to the reaction mixture in a number of different forms. For example, formaldehyde gas, aqueous or alcoholic solutions of formaldehyde, paraformaldehyde and other formaldehyde yielding polymers may be used. In most cases it has been. found preferable to use an excess of formaldehyde usually up to about 4 or 5 mols in order to insure completeness of the condensation reaction.

A variety of solvents, alkaline condensation catalysts and reaction conditions may also be employed. As solvents, either aqueous or anhydrous lower aliphatic alcohols are particularly adv-antageous but moist dialkyl ethers and dioxanewater mixtures may also be used. The alkaline condensation catalyst used in this phase of the invention may be organic bases, inorganic bases or inorganic salts of acidic or pseudo acidic organic compounds. Some representative types of these catalysts are the hydroxides, oxides, carbonates, bicarbonates and amides of alkali or alkaline earth metals; alkali metal alkoxides; alkaline earth alkoxides; alkali metal phenolates; alkali metal salts of lower aliphatic carboxylic acids; organic tertiary amines and quaternary ammonium hydroxides of organic tertiary amines. In general, the weakly alkaline catalysts such as sodium bicarbonate, potassium bicarbonate, calcium hydroxide, pyridine, triethylamine, N-ethylmorpholine, N,N-dimethylaniline and the like are preferred since they make the reaction much easier to control. When strongly alkaline catalysts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium methylate, sodium ethylate and the like are used, care must be taken to remove or inactivate the catalyst as soon as the reaction is completed in order to prevent the conversion of the desired product to the: corresponding methylene bis compound by dehydration and coupling reaction. Although the amount of catalyst is not critical and can vary from a few hundredths or thousandths of a mol to one mol or more it is preferable from the stand- :point of yield to use only enough to bring about arelatively rapid reaction. In most cases 0.05

mol or less is sufficient. Y The temperature used in carrying out this methylolation reaction as well as the time required for its completion varies with the catalyst used. In general, the reaction can be carried out at a temperature between about 0 and 75 C. in a time varying from a few minutes to several When strongly alkaline catalysts are used complete in a few minutes at room temperature or below. However, when mildly alkaline catalysts are employed the reaction is not so rapid and usually requires from fifteen minutes to several hours at room temperature or slightly above, that is. at about 25 to C.

The reduction of the biphenylyl-a-acylamidofl-hydroxy or p-acyloxy ethyl ketone compounds to the corresponding 1-biphenylyl-2-aclyamido- 3-hydroxy or B-acyloxypropane-l-ol compounds shown by Step IV (a) and (b) in the above diagram can be carried out in several different ways. For example, it may be carried out using hydrogen gas in conjunction with a metal hydrogenation catalyst; an oxidizable aluminum alkoxide or nascent hydrogen generated in the reaction mixture by the interaction of a metal with an acid,

lower aliphatic alcohol, water or mixtures of the same.

In carrying out the hydrogenation by catalytic means hydrogen pressures ranging from about 25 to 4000 lbs/sq. in. and temperatures below about 100 C. can be used. However, in order to lessen hydrogenolysis of the product it is preferable to keep the temperature and pressure as low as possible. A temperature of about 25 to 45 C. and a pressure of about .40 to 1000 lbs./sq. in. are usually sufiicient to bring about reduction within a reasonable time and hence are preferred. Some examples of the hydrogenation catalysts which can be employed are Raney nickel, palladium, palladium oxide, platinum, platinum oxide and the like while suitable solvents for the reduction include lower aliphatic alcohols and aqueous solutions of the same, lower aliphatic acids, dioxane-water mixtures and the like.

When using the nascent hydrogen method of reduction metals or alloys such as sodium, potassium, calcium, sodium amalgam, potassium amalgam, iron and the like are caused to react with the solvent used for the reaction to produce hydrogen in the reaction mixture. Some examples of the solvents which can be used are lower aliphatic alcohols such as methanol, ethanol and isopropanol; lower aliphatic acids such as acetic acid; aqueous mixtures of either lower aliphatic alcohols or acids; moist dialkyl ethers such as v acid-water mixtures.

moist diethyl ether and lower aliphatic alcohol- Specific combinations of these metals and solvents which have been found to be particularly effective in bringing about the reduction of the ketonic compounds are sodium, potassium or calcium and absolute ethanol or methanol; sodium or potassium amalgam in moist ether, ethanol or acetic acid; and iron in dilute ethanol containing acetic acid.

When an oxidizable aluminum alkoxide is used as a recluctant for the ketonic compounds of the invention the reaction is carried out at a temperature between about 20 and 125 C. in a lower aliphatic alcohol which is preferably the one corresponding to the alkoxide. The use of alkoxides of secondary alcohols such as isopropanol and secondary butyl alcohol is preferred since these alkoxides are more readily oxidized and hence milder reaction conditions can be employed. The amount of the oxidizable aluminum alkoxide in relationship to the quantity of the ketonic compound to be reduced can be varied within rather large limits. In most cases it is seldom necessary to employ more than about three equivalents of the alkoxide but, if desired, as little as one equivalent to as much as twenty or thirty equivalents can be used, When using an alkoxide derived from a secondary aliphatic alcohol in a solvent of the alcohol corresponding to the alkoxide the preferred method of bringing about the reaction is to reflux the reaction mixture containing one or slightly more equivalents of the aluminum alkoxide and to distill the oxidized alcohol oil (a lower aliphatic ketone) as it is formed in the reaction mixture.

Although all of the foregoing methods of reduction can be used with about equal success in most instances, there are 01 course instances where the use of one method is preferable. Similarly, the optimal conditions or reagents used in conjunction with one method vary somewhat in the individual cases. For example, where the ketonic compound to be reduced contains a halogen or nitro substituent in the phenyl ring it is preferable to use the oxidizable aluminum alkoxide method of reduction since the metallic catalysts used in the catalytic method of hydrogenation and some of the metals (such as sodium, potassium and the like) used in the nascent hydrogen method of reduction tend to remove the halogen atom during the reaction.

The conversion of the biphenylyl-a-acylamido-' s-hydroxy ethyl ketone compounds to the corresponding ,B-acyloxy derivatives shown by Step V in the above diagram can be affected by treating the p-hydroxy ketone with an acyi halide or acyl anhydride under substantially anhydrous conditions either alone or in the presence of an acylation catalyst such as an inorganic base, an alkaline salt of an organic acid, an organic tertiary base, an aromatic sulfonic acid or sulfuric acid. The acylation can, in general, be carried out at a temperature varying from about to 140 C. but the preferred temperature for the reaction is between about 60 and 120 C. An inert organic solvent such as benzene, petroleum ether, toluene and the like can be used for the reaction if desired, although in most cases it is more expedient to omit the use of a solvent and to merely use an excess of the acylating agent. Some of the catalysts which can be used to bring about the reaction in a shorter period of time are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium acetate, pryidine, quinoline, triethylamine, N-ethylmorpholine, N-methylpiperidine, N,N-dimethylaniline, p-toluenesulfonic acid and sulfuric acid.

The hydrolysis of the mono, di or tri acylated 1 biphenylyl 2 aminopropane 1,3 diol compounds to the corresponding 1-biphenylyl-2- aminopropane-1,3-dios shown as hydrolysis (a), (b) and (c) in the above diagram can be effected with either alkaline or acidic hydrolysis catalysts or reagents. This hydrolysis reaction can be carried out using the unresolved, the racemic structural or the individual resolved optical and structural isomers of the acylated amino diols as starting materials. Dilute mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric and sulfuric acids are the preferred hydrolytic agents as they are more efllcient in bringing about complete hydrolysis in a shorter time with less destruction of the final product. When acidic hydrolytic reagents such as the aforementioned mineral acids are employed the 1- biphenylyl-2-aminopropane-1,3-diol product is present in the reaction mixture in the form of an acid addition salt and it can either be isolated as such or the salt can be neutralized and the amino diol isolated as the free base. Among the many alkaline reagents which can be used to bring about the hydrolysis are the alkali or alkaline earth metal hydroxides, oxides, carbonates, amides, alkoxides and phenolates;

quaternary ammonium hydroxides and strong tertiary organic nitrogen bases.

The hydrolysis of the dior triacylated'lbiphenylyi 2 amino-propane 1,3 diol compounds to the corresponding l-biphenylyl-Z-acylamidopropane-l,3-diols as shown in the above diagram as hydrolysis (d) and (e) involves selectively hydrolyzing the O- acyl groups present in the polyacylated amino diol compound. This is accomplished by treating the polyacyiated amino diol starting compound with a strongly alkaline material dissolved in an aqueous solution containing a water-miscible organic solvent at about -20 to +50 C. Some of the strongly alkaline materials which can be used are the alkali metal hydroxides, the alkaline earth metal hydroxides and the alkali metal carbonates.

This transformation can also be effected in a similar manner using a mildly alkaline'material such as an alkali metal bicarbonate and heating the mixture at about 75 to C. Suitable organic solvents for use in this reaction are, in general, lower aliphatic alcohols such as methanol, ethanol, isopropanol, isobutanol, lower aliphatic ketones such as acetone, methylethyl ketone and cyclic ethers such as dioxane. The preferred method of carrying out this selective hydrolysis is to maintain the temperature in the neighborhood of 25 C and to use only a slight excess over the amount of strongly alkaline material necessary to bring about the hydrolysis of the O-acyl group or groups. When carrying out the reaction in this fashion, the

solvent of choice is an approximately 50% aqueous' solution of a lower aliphatic alcohol such as methanol or a lower aliphatic ketone such as acetone.

As will be seen from the above diagram (see acylations (a), (b) and (c)), the completely acylated amino diols of the invention can be prepared by acylation of the free amino diol, its N-acylamino or its N-3-O-diacyl derivatives. The individual isomers or the optical racemates of the structural forms of the aforementioned starting materials as well as the unresolved form of the starting materials can be employed in the practice of this phase of the invention. Generically speaking the process for preparing these completely acylated amino diols involves acylating a compound of the formula,

OH NHR:

where R, Ra, R: and n have the same significance as given above.

As acylating agents either acyl halides or acyl anhydrides can be used. These acylating agents which are preferably employed under substantially anhydrous conditions can be used alone or in conjunction with alkaline catalysts such as the alkali or alkaline earth metal hydroxides, carbonates and oxides, the organic tertiary bases and the like. Some specific examples of suitable alkaline catalysts are sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate, calcium oxide, pyridine, dimethylaniline, N-ethylpiperidine, N- ethylmorpholine, quinoline, triethylamine and the like. In general, when no alkaline catalyst is employed the reactants must be heated to- I Rn gether in order to bring about the reaction within uremic catalyst is employed, heating is usually not necessary as the reaction proceeds with sut- 'iicient rapidity at moderate temperatures, that is, below about 50 C. In some instances, however, where the acyl halide or anhydride is not particularly reactive it is advantageous to carry out the reaction at a temperature above about 50 C. 1

This acylation process can also be carried out in an aqueous medium. This is most conveniently accomplished by using a two-phase reaction mixture, that is, one consisting of water and a water-immiscible organic solvent such as ethyl acetate, ether, chloroform and ethylene dichloride. In such a case it is preferable to carry out the reaction at about 25 C. or below and to employ a weakly alkaline material in conjunction with the acyl halide or anhydride. Some examples of the weakly alkaline materials which can be used are calcium carbonate, magnesium carbonate, barium carbonate and the like.

The 1 biphenylyl 2 acylamido 3 acyl oxypropane-l-ol compounds or the invention can be prepared as shown by the above diagram (see acylations (d) and (e)), by acylating the corresponding free amino diol or its n-acylamido derivative. These starting materials which have the general formula,

m- Jm-en-cmoH [GO] where R, Ba and n have the same significance as given above, maybe used in their unresolved form or in the form oi! their individual separated isomers or as an optical racemate 01 one of the two structural i'orms. As acylating agents,

acyl anhydrides orhalides either alone or in con junction with alkaline catalysts may be used.

In carrying out the acylation under substantially anhydrous conditions with an acyl anhydride, the reaction mixture is heated at about 60 to 135 C. for a short period or time. In most cases the reaction mixture need only be heated for about five to thirty minutes. If desired, the reaction can even be carried out at lower temperatures by allowing the reaction to proceed for a proportionately longer period 01' time. In general, however, the reaction is preferably carried out at about 70 to 100 C. for about one-half hour.

When an acyl halide is used asthe acylating agent under substantially anhydrous conditions, and in the absence 'of a catalyst, the reaction is carried out at a temperature below about 50 C. As a precaution against side reactions it is preferable to use only a slight excess of the acyl halide over that required for the reaction with the terminal hydroxyl group, and, in the necessary instances, the amino group.

When an alkaline catalyst is used in conjunction with either an acyl halide or anhydride, the reaction can be carried out at a lower temperature and within a shorter time. In general, the quantity of acylating agent should not be much in excess of that required to react with the terminal hydroxyl group and, where a free diol is used as the starting material, with the amino group. The preferred temperature for the reaction is in the range of 20 to 35 C. although the mixture can be heated to as high as 100 C.

v if desired.

11 an alkaline catalyst is employed, the acylation can be carried out using an acylhalide in an aqueous medium at a temperature between about 0 and 35 C. As in some of the previously described modifications of'the present acylation process, it is preferable to use only a slight excess of the acylating agent or the theoretically required amount. when the acyl groups are of a type which are readily hydrolyzed such as.

a lower aliphatic acyl group, the alkaline catalyst should be a relatively weak alkaline substance such as barium carbonate, calcium carbonate, magnesium carbonate, sodium acetate or the like. However, where the acyl groups are of a type more resistant to hydrolysis, such asbenzoyl or substituted benzoyl radicals, strongly alkaline catalysts such as sodium hydroxide and the like may be employed.

Some specific examples of the alkaline materials which can be used in the above described acylation processes'are sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, calcium hydroxide, calcium carbonate, barium carbonate, magnesium carbonate, barium hydroxide. pyridine, triethylamine, quinoline, N-ethylmorpholine, N-methylpiperidine and the like.

The 1-biphenylyl-2-acylamidopropane-1,3-dio1 compounds of the invention can be prepared as has been described above by reduction or hydrolytic processes. These products can also be produced by mono-acylation of the corresponding l-biphenylyl-2-aminopropane-1,3-diol as shown in the above diagram under acylation (f). A This latter method of preparation is of particular value where the product desired is an optically active isomer, since it is necessary to convert the optically racemic acylated products of the invention to the free amino diol in order to separate the optical racemate into its component isomers. It is also of value where the N-acylamido compound produced by the reduction or hydrolytic processes contains an acylamido group other than the one desired in the final product. In such a case, the N-acylamido compound is hydrolyzed to the free amino diol (hydrolysis (a) in the above diagram) and then the amino group of the free amino diol reacylated with the desired acyl group in accordance with the present monoacylation process.

In carrying out this mono-acylation process the free amino diol is treated with an acylating agent under mild acylating conditions. In order to eliminate the possibility of poly-acylation it is preferable to use either an ester-type acylating agent under substantially anhydrous conditions or an acyl anhydride or halide under substantially anhydrous conditions at a low temperature or an acyl anhydride or halide in a mildly alkaline aqueous reaction medium.

Where an acyl ester is used as the acylating agent the optimum reaction conditions are contingent upon the reactivity of the ester per se and also upon the reactivity of the potentially active substituents of the acyl portion of the molecule. Thus, for esters of a given' acid the lower aliphatic alkyl esters are morereactive than higher alkyls and are, therefore, the preferred type, the methyl esters being the preferred member of the lower alkyl types. In the case of a; highly active ester of the type of methyl dichloracetate, the reaction is substantially complete in periods of one-half to four hours at temperatures varying from 100 C. to C. On the other hand, a relatively inert ester such as methyl benzoate does not react with the amino diol starting materials in practical time intervals so that a catalyst such as an alkali metal alcoholate is added to accomplish this in a reasonable time. Again, while methyl dichloroacetate reacts when heated with the amino diols to form amides without substantial side reactions, the bromine atom of the corresponding methyl dibromoacetate at 100 C. reacts further to form cyclic amide ethers which are u'ndesirable products. This side reaction is avoided by using a lower reaction temperature, that is, 40 to 60 C., in this instance or by use of an inert diluent such as alcohol. Y

When the acylation is carried out using an acyl anhydride or halide under substantially anhydrous conditions, the temperature should be kept below about 15C. and preferably in the neighborhood of about C. It is also preferable from the standpoint of increased yields and ease in controlling the temperature to carry out the reaction in an inert organic solvent. Some suitable solvents for this purpose are esters of low fatty acids such as ethyl acetate, lower aliphatic ketones such as acetone and methyl ethyl ketone, cyclic ethers such as dioxane, hydrocarbons such as benzene and toluene, halogenated aliphatic hydrocarbons such as ethylene dichloride and chloroform.

The acylation in an aqueous reaction medium using an acyl halide or anhydride as the acylating agent is affected at a pH greater than 7 and ate. temperature below the boiling point of the mixture. Water alone or water together with a water-miscible or water-immiscible organic solvent is used as the reaction medium. In general, water alone is satisfactory in most instances but where the amino diol starting material is quite insoluble it is sometimes advantageous to add a water-miscible organic solvent such as methanol, ethanol, or acetone to increase its water solubility and to facilitate the reaction. In other instances, however, where the acylating agent is quite reactive it is sometimes preferable to employ a twophase system in order to minimize the exposure of the final product to the unreacted acylating agent. This is accomplished by carrying out the reaction in a mixture of water and a water-immiscible organic solvent such as ethyl acetate, ether, benzene, xylene, chloroform, carbon tetrachloride and the like. Some examples of the alkaline materials which can be used for maintaining the alkalinity of the reaction mixture are the alkali metal acetates, bicarbonates, carbonates, hydroxides and phosphates, the alkaline earth hydroxides and organic bases such as pyridine, N-ethyl morpholine, triethylamine and the like.

Although several different procedures for carrying out the N-monoacylation of the amino diol starting compounds have been described above, there are, of course, instances where the use of one method or procedure is preferable. Similarly, the optimal conditions or reagents used in conjunction with one procedure vary somewhat in the individual cases. For example, when an acyl group containing at least one a-halogen atom is desired on the amino nitrogen atom in the final product the choice of the method of acylation is to some extent dependent upon the reactivity of the halogen atom or atoms. Thus, in the case of the mono, di and tri-fluoro and -chloro acetic acids, the halogens are relatively inert and the acyl amido diol compounds of the invention may be prepared by any ofthe methods described above with about equal success. How- 'ever, where the halogen atoms are more reactive,

. 12 as in the case of the a-bromo and a-lOdO aliphatic acids, the preferred and best method of preparing the corresponding acylamido diol compounds is to react the amino diol with a haloacyl halide in a substantially anhydrous organic solvent such as ethyl acetate.

As pointed out above, the amino diols of the invention and their acylated derivatives can exist in structural as well as optical isomeric forms.

Where a particular optical isomeric form or optical racemate of one of the two structural forms of these products is desired-it is necessary to separate the unresolved amino diol or acylated amino diol into its two component structural isomers. This is accomplished quite readily and completely by utilization of the difierences in solubility of the two forms in water, organic solvents or in water-organic solvent mixtures. Some of the organic solvents which can housed in this fractional crystallization or solubilization are lower aliphatic alcohols, acetone, chloroform, ethyl acetate and the like. In some cases, the solvent solubility differential of the two forms is not great enough to afford a clean-cut separation of the two structural isomers and in these cases it is preferable to convert the isomer mixture of the free amino diol or acylated amino diol into another acylated derivative of the amino diol whose structural isomers differ more markedly in their solubility characteristics. The structural isomers of this new acylated amino diol can then be separated by fractional crystallization and the appropriate structural form of the product so obtained converted either by acylation or hydrolysis to the desired structural form of the free amino diol or acylated amino diol.

Where a particular optical isomer of the amino diol or acylated derivative thereof is desired the corresponding individual regular or pseudo structural form of the 1-biphenylyl-2-aminopropane- 1,3-diol is resolved into its optical isomers via an optically active acid addition salt. This resolution which must be carried out on the free amino diol is performed by forming an acid addition salt of the racemic amine with an optically active acid such as (d) -tartaric, (D-tartaric, (d)-mandelic, (l) -mandelic, (d) -bromcamphor sulfonic, (l) -bromcamphor sulfonic, (d) -camphor sulfonic and (l) -camphor sulfonic, separating the two isomeric salts by recrystallization from a solvent such as a lower aliphatic alcohol or mixtures of the same with water or other organic solvents and then regenerating the individual optical isomers from the separated optically active acid addition salts by neutralizing each one separately. When carrying out this resolution it is desirable, but not absolutely necessary, to choose the form of the optically active acid so that the desired optical isomer will separate from the crystallization solution first.

The products of the invention are useful as intermediates in the preparation'of other organic compounds. They are of particular value in the preparation of organic compounds possessing antibiotic activity against micro-organisms of the Rickettsia type. Some of the N-acyl amino diols of the invention are per se antibiotics and exhibit novel antibiotic activity against various Rickettsia and gram negative bacteria. One of the products which is particularly outstanding in this respect is (1)-:,b-1-bipheny1yl-2-dichlor0- acetamidopropane-1,3-diol.

The invention is illustrated by the following examples.

13 Example 1 (a) 26 cc. of bromine is added slowly with stirring to 100 g. of e-biphenylylmethyl ketone in 500 cc. of carbon tetrachloride at room temperature. As soon as the bromine color has been discharged from the solution the carbon tetrachloride is evaporated in vacuo to obtain the desired 4-bi-phenylyl bromomethyl ketone of formula,

o O-O-ii-cnxcmnM-m (c) 1'75 g. of the 4-biphenylyl bromomethyl ketone hexamethylene-tetramine complex is added to 200 cc. of concentrated hydrochloric acid in 1 liter of absolute alcohol and the mixture stirred overnight. The insoluble hydrochloride salt of 4-biphenylyl aminomethyl ketone is collected by filtration, washed with a small amount of cold water and dried at room temperature. The formula of this product is (d) The 4-biphenylyl aminomethyl ketone hydrochloride prepared in (c) is dissolved in 500 cc. of glacial acetic acid and 300 cc. of acetic anhydride. 150 g. of sodium acetate is added in small portions with stirring. After the addition has been completed the solution is diluted with water and the 4-biphenylyl acetamidomethyl ketone which separates collected and recrystallized from methanol; M. P. 154-5 C. The formula of this compound is (e) 58 g. of 4-biphenylyl acetamidomethyl ketone is mixed with 300 cc. of methanol and 75 cc. of 40% neutral formalin. 2 g. of sodium bicarbonate is added and the mixture stirred at room temperature for about an hour during which time the desired solid product separates. The droxyethyl ketone of formula,

OOiLdH-cm-on is collected and purified by recrystallization from ethyl acetate; M. P. 166-7 C.

(j) 50 g. of 4-biphenylyl-e-acetamido-p-hydroxyethyl ketone is mixed with 75 g. of aluminum isopropylate and 1 liter of isopropanol and the mixture heated under reflux for five hours. During the refluxing period the acetone which is formed is distilled OK and a stream of nitrogen is passed through the solution. The isopropanol is distilled from the reaction mixture under reduced pressure and the residue treated with about 1 litel of water. The mixture is heated to boiling to insure complete precipitation of the insoluble 4-biphenylyl-a-acetamido-B-hyl4 v aluminum hydroxide, filtered while hot and the filtrate allowed to cool. The (dl) --1-(4-biphenylyl) -2-acetamido-propane-1,3'-diol which separates from the-cool solution is collected by filtration and purified by recrystallization from 40% ethanol; M.P. -1 C. The formula of this product is O .0 H NH-JE-C Ha (dl form If desired, the corresponding (dli-reg. isomer may be recovered from the aqueous filtrates.

(g) 12 g. of (dl) --1-(4-biphenylyl)-2-acetamidopropane-lB-diol is heated with 400 cc. of

5% hydrochloric acid for twelve hours. The reaction mixture is cooled and the hydrochloride salt of (dl) --1-(4-biphenylyl) 2-aminoprcpane-1,3-diol which separates collected and washed with a small amount of water. The hydrochloride salt thus obtained is dissolved in water and the solution treated with an excess of ammonium hydroxide. The (dl)-\p-1- (4-biphenylyl)-2-aminopropane-l,3-diol free base which separates is collected and purified by re crystallization from water; M. P. 149-50 0. The

formula of this product is 0H NH:

O-O-dn-dra-cmon I (h) 3 g. of (dl)--1-(4-bipheny1yl)-2-aminopropane-1,3-diol is dissolved in a minimum amount of water containing a small amount of methanol and the resulting solution treated with an aqueous solution containing an'equivalent amount of (d)-tartaric acid. The solution is evaporated to dryness in vacuo and the residue fractionally crystallized from a minimum amount of hot methanol. The first isomer to separate from the solution in crystalline form is the (d) -tartaric acid salt of (l) -\p -1-(4-biphenylyl)- 2-aminopropane-L3-diol. The (d)=-tartaric acid salt of (d) -\p-1 -(4-biphenylyl) -2-aminopropane- 1,3-diol is recovered from the filtrates after removal of the salt of the (l) -isomer.

The (d)-tartaric acid salt of (l)-\//-1-(4-biphenylyl) -2 -aminopropane-1,3-diol obtained above is dissolved in water, the solution made alkaline topH 9 with sodium hydroxide solution and the precipitated (l)--1-(4-biphenylyl) -2- aminopropane-1,3-diol free base collected. The formula of this product is 1 form By decomposing the (d)-tartaric acid salt of (d) 1 (4 biphenylyl) 2 aminopropane 1,3-diol in the same manner as described above for the (l) isomer, one obtains the free base of (d) -/-1-(4-biphenylyl) -2-aminopropane-L3- diol. In an analogous manner the (dl) --l-(4- biphenylyl) -2-aminopropane-1,3-diol may be re- 1 (l) 1 g. of (l) --1-(4-biphenylyl) -2-aminopropane-1,8-diol is heated with 3 cc. of methyl dichloracetate on a steam bath for one-half hour. The reaction mixture is evaporated to dryness in vacuo and the residue recrystallized from water to obtain the desired (1) --1-(4-b'iphenylyl) 2-dichloracetamidopropane-1,3-diol of formula,

on Nrr- -cnch OOJm-dn-cmon (1)-W form (1) 2 g. of (d1)--1-(4-biphenylyl-2-aminopropane-1,3-diol is heated with cc. of methyl dichloroacetate on a steam bath for about onehalf hour. The reaction mixture is evaporated to dryness in vacuo and the residue recrystallized from water to obtain the desired (dl)--1-(4- biphenylyl) 2 dichloroacetamidopropane 1,3-diol; M. P. 149-50 C. Mixed M. P. with base from (g) l30-1 C. This compound has the formula,

when...

(61) 11 form (It) 0.008 g. of sodium dissolved in methyl alcohol is added to a mixture consisting of l g. of (l) 1p 1 (4 biphenylyl) 2 aminopropane 1,3-diol and 7 g. of methylbenzoate in about 50 cc. of methanol and the mixture heated on a steam bath for twenty minutes. The solution is diluted with 3 volumes of 1 N hydrochloric acid and the oily precipitate which solidifies collected and. purified by recrystallization from either water or ethyl acetate or a mixture of the same. The product thus obtained is (1)- 0-1-(4- biphenylyl) -2-benzamidopropane-1,3-diol which has the formula,

O 0.. 0 laim...

(1)-1k form (I) 2 g. of (dl)-//-1-(4-biphenylyl) -2-aminopropane-1,3-diol is added to a mixture composed of 6 cc. of aceticanhydrid and 6 cc. of dry pyridine and the resulting mixture heated at 100 C. for about one-half hour. The reaction mixture is evaporated to dryness in vacuo and the residue recrystallized from methanol to obtain the triacetate of (d1)-1//-1-(4-biphenyly1)-2-aminopropane-1,3-diol of formula,

NH- CH: O

oOdn-( m-cmoc o H! (122) 2 g. of (dl)-i//-1-(4-biphenylyl) -2-aminopropane 1,3-diol is heated with an excess of acetic anhydride at 70 C. for fifteen minutes. The reaction mixture is evaporated to dryness in vacuo and the residue recrystallized from ethanol. The white crystalline produce thus obtained is (d1) 41 l (4 biphenylyl) 2 acetamido 3-acetoxypropane-l-ol of formula,

on Nrr- -om (d1)-'// form (n) 1 g. of (dl)--1-(4-biphenylyl)-2-acetamido-3-acetoxypropane-1ol is added to a mixture composed of 4 cc. of acetic anhydride and 4 cc. of dry pyridine and the resulting mixture is evaporated to dryness in vacuo and the residue recrystallized from methanol to obtain the desired triacetate of (d1)-p-1-(4-biphenylyl)-2- aminopropane-l,3-diol of formula,

NH- CH3 0 a o OOn-dn-cmo 0 cm (dl)-1,l/ form This product is identical in all respects with th'e product obtained in (1) above.

(0) A two-phase system consisting of 60 cc. of 0.5 N potassium hydroxide and an equal volume of ether, 1.25 g. of (dl)--1-(4-biphenylyl)-2- aminopropane1,3-diol and 0.93 g. of p-nitrobenzoyl chloride is shaken at 0 C. for ten minutes. The insoluble product which separates from the reaction mixture is collected, washed with water and purified by recrystallization from alcohol. This product is (dl)--l-(4-biphenylyl) 2 (p' nitrobenzamido)propane- 1,3-diol of formula,

(d1) 1% form (p) 1 g. of (dl)--1-(4-biphenylyl)-2-aminopropane-1,3-dlol in about cc. of ethyl acetate is treated with 1 cc. of furoyl chloride at 0 C. After one-half hour water is added, the ethyl acetate layer separated, washed with dilute acid, then with sodium bicarbonate solution and finally with water. The ethyl acetate is removed by distillation in vacuo and the residue recrystallized from water to obtain the desired (d1) --l- (4 biphenylyl) 2 furamidopropane 1,3 dlol of formula,

0 Neal! 0 on i (dB-w form 'p-1-(4 biphenylyll z-ap dimethylacrylamidopropane-1,3-diol of formula,

(dl)- form I (r) .1 g. of succinic anhydride is added to.2.4 g. of (dl) --1-(4-biphenylyl) -2-aminopropane-1,3- diol in the minimal amount of water and .the mixture heated for thirty minutes. The reaction mixture is allowed to stand overnight at 25 C.

and the crystalline (d1)--1-(4-bipheny1y1)-2-pcarboxypropionamidopropane-1,3-diol collected. This product has the formula,

0 0H NH- -omomiLon OO-drr-rtm-omon (dB- ll form and may be purified, if desired, by recrystalliza tion from water. I

' Example 2- (a) 26 cc. of bromine is added slowly with stirring to 100 g. of 3-biphenylyl methyl ketone dissolved in 500 cc. of chloroform. As soon as the bromine color has disappeared the chloroform is removed by distillation in vacuo to obtain the desired 3-biphenylyl bromomethyl ketone of formula,

o iii-cram (c) 1'75 g. of the 3-biphenylyl bromomethyl -ket0ne hexamethylenetetramine complex prepared as described above is mixed with a cold solution of 1 liter of absolute alcohol and 200 cc. of concentrated hydrochloric acid and the mixture stirred overnight at room temperature. The solid product which consists of the hydrochloride salt of 3-biphenylyl aminomethyl ketone is collected, washed with 200 cc. of ice cold water to remove the ammonium chloride and dried. The formula of this compound is O L-C HINHrHCl (d) A mixture consisting of g. of 3-biphenylyl aminomethyl ketone hydrochloride, 50 g. of benzoic anhydride and 6 g. of sodium acetate is heated to about45 C. and stirred as small amounts of ice and water are added from time to time. After about one hour the mixture is diluted with 300 cc. of water, cooled, adjusted to pH 8 with sodium hydroxide and the desired B-biphenylyl benzamidomethyl ketone collected.

After washing with water, this product which has the formula,

0 o ti-omNntLo is dried in vacuo.

(e) A mixture consisting of 31.5 g. of 3-biphenylyl-benzamidomethyl ketone. 1 8. of sodium bicarbonate and 6 g. of paraformaldehyde in 300 cc. of methanol is warmed at to C. for one-half hour. The reaction mixture is allowed to stand for one hour and then poured into 1% liters of ice water. The precipitated product is collected, washed with water and purified by re.- crystallization from ethyl acetate or ethanol to obtain the pure 3-biphenylyl-a-benzamido-p-hydroxyethyl ketone of formula,

tin-omon (f) 30 g. of 3-biphenylyl-a-benzamido-p-hydroxyethyl ketone is dissolved in ethanol and 5 g. of Raney nickel hydrogenation catalyst added to the solution. The mixture is shaken with gaseous hydrogen under 50 1bs./sq. in. pressure for three to four hours at room temperature. The catalyst is removed by filtration, the residual catalyst washed well without ethanol and the illtrate evaporated to dryness in vacuo. The residue thus obtained consists of the unresolved l-(3 biphenylyl) 2 benzamidopropane 1,3-

0H NIL-EEO H- H-C HIGH 'diol of formula,

Unresolved Crystallization of the unresolved 1 (3 biphenylyl) -2 benzamidopropane 1,3 diol from ethanol yields as the first crystalline product the (dl)--l-(3-biphenylyl 2 benzamidopropane- 1,3-diol of formula,

0 O on H- H-OHzOH (dl)- form If desired, the ((11) -reg. 1 (3 biphenylyD-2- benzamidopropane 1,3 diol can be recovered from the filtrates after the removal of the (d1) isomer.

(g) 10 g. of (dl)-/-l-(3-biphenylyl)-2-benzamidopropane-1,3-diol is heated under reflux with 400 cc. of 5% hydrochloric acid for twelve hours. The solution is cooled and the hydrochloride salt of (d1) p 1 (3 biphenylyl) 2- sminopropane-LS-diol which separates collected and dissolved inwater. The solution is made alkaline with concentrated ammonium hydroxide and the free base of (d1)--1-(3 biphenylyl)-2- aminopropane-L3-diol'. collected and recrystallized from water. The formula of this compound is an-w form (It) 5 g. of (dl)--1-(3-biphenylyl)-2-aminopropane-1,3-diol and 5.3 g. of methyl dibromoacetate in 20 ml. methanol is heated at 50 for about one hour. The reaction mixture is evaporated to dryness, washed with carbon tetrachloride, and the residue recrystallized from water to obtain the desired (d1) --1-(3-biphenylyl) 2-dibromacetamidopropane-l,3-diol of formula,

vacuo. The residue which consists of 3-biphenylyl-urbenzamido-p-acetoxyethyl ketone of formula,

H-CHzO C-CH:

is washed with water and purified by recrystallization from ethanol.

(1) A mixture consisting of 3 g. of 3-biphenylyl-a-benzamido-fl-acetoxyethyl ketone, 0.3 g. of Raney nickel hydrogenation catalyst and sumcient ethanol to dissolve the ketone is shaken at 25 C. with gaseous hydrogen under a pressure of about 50 lbs/sq. in. until 1 mole equivalent of hydrogen has been absorbed. The reaction mixture is filtered to remove the hydrogenation catalyst, the catalyst extracted with boiling ethanol and the combined filtrates evaporated to dryness in vacuo to obtain the unresolved 1-(3-biphenylyl)-2-benzamido-3-acetoxypropane-1-ol of formula,

. IH E O H-CHaO C 8 Unresolved This unresolved product is taken up in the m'ini mal amount of boiling ethanol or ethyl acetate and the solution chilled. The crystalline product which separates is collected, washed with a small amount of cold solvent and dried. It is (db-#1- 1-3(3-blphenylyl) -2 benzamido-3 acetoxypropane-l-ol of formula,

o I Q 0 E-OHIOE-OH' (dB-p form (k) 1 g. of (d1)-\//-1-(3-biphenylyl)-2-benzamido-3-acetoxypropane-1-ol is heated under reflux for twelve hours with 35 cc. of 5% hydrochloric acid. The reaction mixture is cooled and the hydrochloride salt of (d1) l/-1-(3-biphenylyl)-2-aminopropane-1,3-diol which separates collected. This salt which is contaminated with a small amount of benzoic acid is dissolved in water, the solution made alkaline with sodium hydroxide and the free base of (dl) -p-1-(3-biphenylyl) -2-amin0propane-1,3-diol of formula,

OH NH! H-- H-CHaOH (dl)- b form collected, washed with water and dried. This product is identical in all respects with the product obtained in paragraph (9) above.

Example 3 (a) 61 g. of 4'-methoxy-4'-biphenylyl bromomethyl ketone dissolved in the minimal amount of chloroform is added to a solution of 30 g. of hexamethylenetetramine in about 400 cc. of ch10- roform. The solid product begins to separate almost immediately and the temperature of the reaction mixture rises somewhat. After allowing the mixture to stand for about two hours the 4'-methoxy-4-biphenylyl bromomethyl ketone hexamethylene tetramine complex is collected, washed with a little chloroform and dried. The formula of this product is o cmoG-O-cmwnom-nk (b) g. of 4'-methoxy-4-biphenylyl bromomethyl ketone-hexamethylene-tetramine complex prepared as described in (a) is mixed with a cold solution of 500 cc. of absolute ethanol and 100 cc. of concentrated hydrochloric acid andthemixture stirred overnight at room temperature. The solid product which consists of the hydrochloride salt of 4'-methoxy-4-biphenylyl aminomethyl ketone contaminated with ammonium chloride is collected, washed with cold .water to remove the ammonium chloride and dried. The formula of this product is o omo-Q-Q-onmm-nm (c) 30 g. of 4'-methoxy-4-biphenylyl aminomethyl ketone hydrochloride is added in small portions to a mixture consisting of 40 g. of

apropos 21 pyridine and 30 g. or phenylacetyl chloride, keepin': the temperature below about C. After stirring ior about one hour 700 cc. of cold water is'added and the precipitated product collected.

are product thus obtained is 4'-methoxy-4-biphenylyl-phenylacetamidomethyl ketone of fortime (d) A mixture consisting of 25 g. of 4'-methoxy-d-biphenylyl phenylacetamidomethyl ketone, 0.2 g. of sodium bicarbonate and 6 g. of paraformaldehyde in 500 cc. of methanol is heated at 40 C. (or about twenty minutes with stirring and then poured into 1500 cc. of ice water. The crude t metlliiily -4 biphenylyl-a-phenylacetamido-p hydroxyethyl ketone which separates is collected, washed with water and purified by recrystallization from alcohol. Theformula of this prodiist is o v NILE-GEO (e) mixture consisting f 12 g. or -i-methoxyi-biphenylylr phenylacetamido-fl-hydroxy ethyl ketone, 10 g. of aluminum isopropylate'and 800 cc. of dry isopropanol is heated under reflux While distilling off a small portion of the isoriropanol from the reaction mixture. Refluxin'e h continued until the distillate gives a negative test for acetone and then the isopropanol distilled on under vacuo. The residue is cooled, treated with ice cold dilute hydrochloric acid and the insoluble, unresolved l-(4'-methoxy-d-biphenylyl) 2 phenylacetamidopropane -1,3-diol collected. The formula of this product is Crystallization of this unresolved product from water or dilute ethanol yields the desired (d1) l-iW-HlGlJhOiW-l biphenylyl) -2-phenylacetamidopropane-l,=3-diol of formula,

it on on l cmoOO-dnn-cmon (dint form cmoWdn-dn-cmon (GU-4 1cm can be purified, if desired, by recrystallization from water.

(a) 1 g. of methoxyacetyl chloride is added to a solution of 2.7 'g. of (d1) --1-(4'-methoxy-4- biphenvlyl)-2-aminoprcpane-l,3-diol dissolved in ethyl acetate at 0 C. After thirty minutes the reaction mixture is washed with a small amount of water, then with a small amount of saturated sodium bicarbonate solution and finally with a fresh portion of water. layer is dried, concentrated to a volume of a few cc. and diluted with petroleum ether until the solution becomes cloudy. The solution is allowed to stand in the refrigerator until the crystalline (d1) -41-1 (4'-methoxy-4-biphenylyl) -2-methoxyacetamidopropane-1,3-di0l separates. This product which has the formula,

0 0H NH-E-C H10 CH:

cmo-OO-dH-dH-omon (db-w form is collected, washed with a small amount of ethyl acetate and dried.

(h) A solution consisting 012.7 g. of (d1) -4/- (4'-methoxy-4-biphenylyl) -2-a.minopropane-l,3- diol, 2 g. of ethyl cyanoacetate, 0.05 g. of sodium methoxide and sumcient methanol to insure solution is heated under reflux for about onehalf hour. 1 cc. of 1 N hydrochloric acid is added, the methanol evaporated and the residue diluted with 25 cc. of 0.1 N hydrochloric acid. The insoluble (d1) ll-1-(4-methoxy-4-biphenylyl) -2-cyanocetamidopropane-1,3-diol of formula,

cmo-QO-dxndu-omon (dB- i form is collected, washed with a small amount of water and dried.

(i) 0.054 g. of sodium methoxide is added to a solution consisting of 2.7 g. of (d1) 1 144- methoxyi-biphenylyl) -2-aminopropane-l,3-diol and 2 g. of ethyl lactate in cc. of dry methanol. The mixture is refluxed for one-half hour, 1 cc. of l N hydrochloric acid added and the methanol removed by distillation in vacuo. The residue istaken up in hot ethyl acetate, the extract filtered to remove the sodium chloride and the filtrate chilled. The crystalline product thus obtained is collected and dried. This product is (61) -\,!/-l- (4'-methoxy-4-biphenylyl) -2,-lacta.mi dopropane-i,3-diol of formula,

cmo-OO-Jm-J: H-CHiOH (GD- form The ethyl acetate free base of (l)all-1-(4'-methoxy-4-biphenylyl)- 2-aminopropane-l,3-diol of formula,

H NH: cHiO-OQ-oH-Jm-CHmH (1)41 form collected.

Example 4 (a) 100 g. of 4'-nitro-4-biphenylyl bromomethyl ketone dissolved in 500 cc. of chloroform is added to a solution of 50 g. of hexamethylenetetramine in 800 cc. of chloroform. The solid product begins to separate almost immediately and the temperature of the reaction mixture rises somewhat. After allowing the mixture to stand for about two hours the 4'-nitro-4-biphenylyl bromomethyl ketone hexamethylenetetramine complex is collected, washed with a little chloroform and dried. The formula of this product is O NOPO-O--CHKCHDIINBI (c) The hydrochloride salt of 4'-nitro-4-biphenyiyl aminomethyl ketone prepared above is added to 250 cc. of glacial acetic acid and 150 cc. of acetic anhydride. 75 g. of sodium acetate is added slowly with stirring and the mixture stirred for about one-half hour. The reaction mixture is diluted with water and the precipitated product collected. Recrystallization, from methanol or ethanol yields the desired 4'-nitro-4-biphenylyl I acetamidomethyl ketone in pure form. The formula of this product is (d) 2 g. of sodium bicarbonate is added to a solution of g. of 4'-nitro-4-biphenylyl acetamidomethyl ketone and 75 cc. of 40% neutral formalin in 450 cc. of methanol and the resulting mixture heated at 45 to 50 C. for about one-half hour. The reaction mixture is poured into 1 liters of ice water and the crude 4'-nitro-4-biphenylyl-- acetamido-fl-hydroxyethyl ketone which separates collected and washed with water. If desired, this product can be purified by recrystallization from methanol. Its formula is o o NH- -CH.

NoOQ -on-cmmz (e) 50 g. of 4'-nitro-4-biphenylyl-a-acetamidop-hydroxyethyl ketone is mixed with 75 g. of aluminum isopropylate and the mixture heated under reflux for five hours. During the reflux period the acetone which is formed is distilled off O OH NH--CH:

(dl)-w form If desired, the more soluble (dl) -reg. isomer may be obtained from the filtrate. In general, a smaller amount of this isomer is formed than of the (dl)-1p form.

(I) 25 g. of (dl) --l-(4'-nitro-4-biphenylyl) -2- acetamidopropane-1,3-diol is added to 800 cc. of 5% hydrobromic acid and the resulting mixture heated under reflux for about twelve hours. The reaction mixture is cooled and the hydrobromlde salt of (dl) I l (4'-nitro 4 biphenylyl) -2- aminopropane -l,3-diol which separates collected and dissolved or suspended in water. The aqueous mixture is treated with an excess of concentrated ammonium hydroxide and the free base of (dl) --1-(4'- nitro 4 biphenylyl) -2- aminopropane-l,3-diol collected and purified by recrystallization from water. The formula 0! this compound is,

OH. NH:

' Mowers-atheism norOo-ea-on-cmon (dl)-g0 form (It) 10 g. of (dl) --l-(4'-nitro-4-biphenyly1)- 2 aminopropane 1,3 diol is dissolved in the minimal amount of hot methanol and added to a methanol solution containing an equivalent amount of (ch-tartaric acid. The mixture is cooled and the crystalline (d) -tartaric acid salt of (1)--l-(4'-nitro-4-biphenylyl)-2 aminopropane-1,3-di0l collected, recrystallized twice from methanol and dried. Fractional crystallization of the reaction mixture filtrate yields additional quantities of the (l)--l-(4'-nitro-4-biphenylyl)-2-aminopropane-1,3-diol (d) -tartaric acid salt and the (d)-//-l-(4'-nitro-4-biphenylyl)-2- aminopropane-l,3-diol (d)-tartaric acid salt. The (d) -tartaric acid saltof the (1)4 isomer is dissolved in water and the solution treated with an excess of concentrated ammonium hydroxide.

The (l) it l-(4'-nitro 4 biphenylyl)2-aminopropane-1,3-diol free base which separates is collected, washed with water and purified further,

25 if desired, by recrystallizationirom water. The iormula of this product is OH NHa NoOO-on-cn-omon Neutralization or basiflcation oi! the corre sponding (d) -salt yields the (d)-ip.-1-(4'-nitro-4- biphenylyl)-2-aminopropane-1,3-diol free base.

If desired, the corresponding (dl) -reg. racemlc mixture can be substituted for the (db-1,0444- nitro 4 biphenylyl) 2- aminopropane-1,3-diol used in the above procedure. In this case the first salt to separate from the solution is the (d)- tartaric acid salt of the (d) -reg.-1-(4'-nitro-4- hiphenylyl) -2-aminopropane-1,3-di0l.

(i) 4 g. of (l) -\p-1-(4'-nitro-4-biphenylyl)-2- aminopropane-l,3-diol is added to 10 cc. of methyl dichloroacetate and the resulting mixture heated for about one-half hour on a steam bath. The reaction mixture is evaporated to dryness and the residue recrystallized from water to obtain the desired (1) -i,l/-1- (4'-nitro-4-biphenylyl) -2-diohloroacetamidopropane-1,3-diol in pure form. The formula of this product is,

OH NH-lL-CHCI:

(1)111 form x t o NoO-Ocm-ln-omg-oO (rm-w form may be purified, if desired, by recrystallization from alcohol.

Example (a) 135 g. of 4-iodo-4-biphenylyl bromomethyl ketone hexamethylene tetramine, complex is mixed with a cold solution of 1 liter of absolute alcohol and 200 cc. of concentrated hydrochloric acid and the mixture stirred overnight at room temperature. The solid hydrochloride salt of 4'- iodo 4 biphenylyl aminomethyl ketone; which separates is collected, washed with cold water to remove the ammonium chloride and dried. The formula of this product is o I-O-Oi-CmNm-HM (b) A mixture consisting of 48 g. of 4'-iodo-4- biphenylyl-aminomethyl ketone hydrochloride, 150 g. oi-benzoic anhydride and 18 g. of dry so dium acetate is heated to about 45 C. and stirred as small amounts of water and ice are added from time to time. After about one hour the mixture is diluted with 1 liter of water, cooled and adiusted to pH 8 with sodium hydroxide. The 4'- iodoi-biphenylyl benzamidomethyl ketone which separates is collected, washed with water and dried. This product has the formula,

(d) 25 g. oi 4-iodo-4-biphenylyl-a-benzamidop-hydroxyethyl ketone is mixed with g. of aluminum isopropylate and 1 liter of isopropanol. The mixture is heated under reflux for five hours during which time the acetone formed is distilled off and a stream of nitrogen passed through the solution. The isopropanol is distilled from the reaction mixture under reduced pressure and the a residue containing the desired 1-(4-iodo-4-biphenylyl) 2-benzamidopropane-l,3-diol treated with about 750 cc. of dilute hydrochloric acid. The insoluble unresolved 1-(4-iodo-4-biphenylyl) -2-benzamidopropane-1,3-diol is collected, washed well with water containing a small amount of hydrochloric acid to remove any remaining aluminum and dried. The formula of this productis I-O-O-(LH- n-ornon Unresolved Example 6 (a) 175 g. of 2'-methyl-4-biphenylyl bromo-. methyl ketone-hexamethylene-tetramine complex is added to 1 liter of methanol and 200 cc. of 12 N sulfuric acid and the resulting mixture stirred overnight at room temperature. The insoluble 2'-methyl-4-bipheny1yl aminomethyl ketone sulfate is collected, washed with a small formula of this product is 0 (20-3-0 HiNHf%HiS06 (b) A mixture consisting of g. of 2'-methyl- 4-biphenylyl aminomethyl ketone sulfate, g.

of p-toluyl anhydride and 18 g. of dry potassium carbonate is heated to about 40 C. and stirred as small quantities of water are added. After stirring for about two hours the mixture is diluted with 1 liter of ice water, cooled and the pH ad:

27 iusted to about 8 with sodium hydroxide solution. The insoluble 2'-methyl-4-biphenylyl-p-toluy1amidomethyl ketone is collected, washed with water and dried in vacuo. The formula of this product is (c) A mixture consisting of 65 g. of 2-methyli-biphenylyl-p-toluylamidomethyl ketone, 300 cc. of ethanol and 75 cc. of 40% neutral formalin is treated with 2 g. of sodium bicarbonate. The mixture is stirred at 35 C. for about one and one-half hours, cooled and the insoluble 2'- methyl 4 biphenylyl a (p toluylamido) p-hvdroxyethyl ketone collected. This product which has the formula,

N.. E- OCH. OOE-(Lrr-cmon is washed with water and dried in vacuo.

(d) g. y of 2-methyl-4-biphenylyl-a-(ptoluylamido) p-hydroxyethyl ketone is heated at about 75 C. for one-half hour with cc. of acetic anhydride containing one drop of concentrated sulfuric acid. The reaction mixture is evaporated to dryness in vacuo, the residue washed with ice water and purified by recrystallization from methanol or ethanol. The product thus obtained is 2'-methyl-4-biphenylyl-a-(ptoluylamido) -fl-acetoxyethyl ketone of formula,

QOE-ln-omoE-cm 0 NH-EG-CH: 0H

Q JQHM If desired, the corresponding (d1) -reg. isomer may be recovered from the aqueous ethanol filtrates.

If 3'-methyl-4-biphenylyl bromomethyl ketone hexamethylenetetramine complex is used instead I 28 of the 2'-methyl-4-biphenylyl bromomethyl ketone hexamethylene complex in (a) and the above succeedingparagraphs, the corresponding 3'-methyl-4-biphenylyl products are obtained.

Example 7 (a) A mixture. consisting of 200 g. of 4'-nitro- 6 methyl 3 biphenylyl bromomethyl ketone hexamethylenetetramine complex, 200 cc. of concentrated hydrochloric acid and 1 liter of isopropanol is stirred overnight at room temperature. The insoluble product is collected, washed with cold water to remove the ammonium chloride and dried. This product is the hydrochloride salt of 4-nitro-6-methyl-3-biphenylyl aminomethyl ketone of formula,

(b) The 4'-nitro-6-methy1-3-biphenyly1 aminomethyl ketone hydrochloride prepared above is added to 500 cc. of glacial acetic acid and 300 cc. of acetic anhydride. 150 g. of sodium acetate is added in small portions with stirring. After about one hour the mixture is diluted with water and the precipitated 4'-nitro-6-methyl-3-biphenylylacetamidomethyl ketone collected. This product which has the formula,

0 O L-C HlNH-E-OHI may be'purified by recrystallization from methanol.

(c) A mixture consisting of 65 g. of 4'-nitro- 6-methyl-3-biphenyly1 acetamidomethyl ketone, 350 cc. of methanol, '15 cc. of 40% neutral formalin and 2 g. of sodium bicarbonate is stirred for about two hours at room temperature. The solution is cooled and the 4'-nitro-6-methyl-3- biphenylyl-a-acetamido- ,8 -hydroxyethyl ketone collected, washed with a small amount of methanol and purified by recrystallization from ethyl acetate or methanol. The formula of this product is 0 O NH-E-CH:

H-CHiOH (d) 40 g. of 4-nitro 6-methyl-3-biphenylyla-acetamido-s-hydroxyethyl ketone is added to g. of aluminum isopropylate in 1 liter of isopropyl alcohol. The mixture is refluxed for five hours during which time the acetone is distilled oil as it is formed and a stream of nitrogen is passed through the solution. At the end of the refluxing period the isopropanol is removed by distillation in vacuo, the residue treated with hot water, the mixture heated to boiling and the aluminum hydroxide removed by filtration. The filtrate is cooled and the crystalline (d1) --1-(4'-nitro-8- methyl-3-biphenylyl) -2-acetamidopropane 1,3- diol collected. The formula of this product is (131)-4/ form The biphenylyl halomethyl ketone-hexamethylenetetramine complexes used as starting materials in the practice of the invention may be prepared by reacting a biphenylyl halomethyl ketone with hexamethylene-tetramine in an inert organic solvent. Examples 1(a) and (b), 2(a) and (b), 3(a) and 4(a) above illustrate the preparation of some specific starting materials used in the practice of this invention.

Some of the subject matter disclosed but not claimed herein is described and claimed in my copending applications Serial Nos. 136,831; 136,832; 136,833; 136,834; 136,835; 136,836; 136,837 and 136,838, all filed January 4, 1950, as continuations-in-part of the instant application,

What I claim is:

1. A compound of the formula,

on NIL-Am GO-cH-oH-CILOH 3. (d1) -11-1-4(biphenylyl-2-dichloroacetamidopropane-1,3-diol.

4. (1) l/-1- (4-blphenylyl) -2-dichloroacetamidopropane-1,3-diol.

5, A 1-(4'-nltro-4-biphenylyl) -2-dihaloacetamidopropane-1,3-diol compound of formula,

vorOOom-oH-omoa 6. (1) -11-1-(4'-nitro -4-biphenylyl) -2-dichloroacetamidopropane-1,3-diol.

'7. (d1) --1-(4'-nitro-4-biphenylyl) 2-dichloroacetamidopropane-1,3-diol.

8. (d1) -\p-1-(4 biphenylyl) 2 acetamidopropane-1,3 diol:

LOUIS L. BAMBAB.

No references cited. 

1. A COMPOUND OF THE FORMULA, 